Advances in the field of redox biology have contributed to the understanding of the complexity of the thiol-based system in mediating signal transduction. The redox environment is the overall spatiotemporal balance of oxidation-reduction systems within the integrated compartments of the cell, tissues and whole organisms. The ratio of the reduced to disulfide glutathione redox couple (GSH:GSSG) is a key indicator of the redox environment and its associated cellular health. The reaction mechanisms of glutathione-dependent and related thiol-based enzymes play a fundamental role in the function of GSH as a redox regulator. Glutathione homeostasis is maintained by the balance of GSH synthesis (de novo and salvage pathways) and its utilization through its detoxification, thiol signalling, and antioxidant defence functions via GSH-dependent enzymes and free radical scavenging. As such, GSH acts in concert with the entire redox network to maintain reducing conditions in the cell. Caenorhabditis elegans offers a simple model to facilitate further understanding at the multicellular level of the physiological functions of GSH and the GSH-dependent redox network. This review discusses the C. elegans studies that have investigated glutathione and related systems of the redox network including; orthologs to the protein-encoding genes of GSH synthesis; glutathione peroxidases; glutathione-S-transferases; and the glutaredoxin, thioredoxin and peroxiredoxin systems.